The protein, CD14, is a myeloid cell-surface glycoprotein which acts as a receptor for bacterial lipopolysaccharide (LPS). It is well documented that monocyte/macrophage activation by lipopolysaccharides via membrane CD14 (mCD14) triggers the release of a variety of pro-inflammatory, immunoregulatory and cytotoxic molecules such as TNF-α, IL-1, IL-6, IL-8, oxygen radical products and nitric oxide. mCD14 is anchored to the cell membrane by a glycosyl-phosphatidylinositol linkage.
In addition to the membrane bound form, soluble CD14 (sCD14) has been identified in normal human blood serum, hereinafter referred to as sCD14. sCD14 exists in two forms, sCD14a (49 kDa) and sCD14p (55 kDa). It has been demonstrated that sCD14 binds LPS and mediates the LPS-induced activation of cells that lack mCD14, including epithelial and endothelial cells and astrocytes, as well as mCD14 expressing cells, such as monocytes and neutrophils. The main source of sCD14 in normal human plasma is the monocyte. A substantial concentration of sCD14 is found in normal human plasma, 2-4 μg/ml.
LPS is believed to be a primary cause of death in humans afflicted with gram-negative sepsis. Sepsis may be defined as a toxic condition resulting from the spread of bacteria or their products from a focus of infection.
Numerous documents in the art describe use of sCD14 or variants/fragments of sCD14 for treatment of sepsis, gram negative bacteria or other related diseases that may be characterized as diseases involving acute inflammation conditions. See e.g. WO9101639, WO92204908, WO9319772, U.S. Pat. No. 5,804,189, WO9620957 and U.S. Pat. No. 5,869,055.
According to the art acute condition may be defined as conditions that are severe and sudden in onset. Symptoms appear, change, or worsen rapidly. A chronic condition, by contract, is continuous or persistent/maintained over an extended period of time. A chronic condition is one that is long-standing, not easily or quickly resolved.
With respect to involvement of sCD14 in diseases involving chronic inflammation, there have been published some studies.
A polymorphism of the CD14 gene, a C-to-T transition at bp-159 from the major transcription start site, seems to play a role in regulating serum sCD14 levels.
The article (Wolfgang K, et al, Journal of the American College of Cardiology, United States—3 Jul. 2002, Vol 40, Nr 1, page 34-42) investigated this polymorphism. They investigated the association of CD14 genotype and plasma levels of soluble sCD14 with risk of stable coronary artery disease (CAD), chronic infections and sensitive markers of systemic inflammation. They found that “sCD14-plasma levels were higher in subjects with TT genotype compared with those with CT or CC genotype (p=0.005)”. Based on analysis of the found individual data the abstract concludes “These results do not confirm an independent relationship between CD14 genotypes or plasma levels of sCD14 and risk of stable CAD in this population”.
Fernandez-Real J M et al published a poster 12 of September 2001 at RASD meeting in Glasgow. The title was “A polymorphism of the CD14 Monocyte Receptor Gene, involved in the inflammatory cascade, is associated with insulin sensitivity”. The abstract reads “C/C type 2 [diabetic] homocygote patients also showed a significant lower insulin sensitivity index than carriers of the T allele”.